Lachowiez Considers the Use of Tagraxofusp in BPDCN as Bridge to SCT With Peers

Curtis Lachowiez, MD (MODERATOR)

Assistant Professor of Medicine

Division of Hematology/Medical Oncology

School of Medicine

Oregon Health & Science University

Portland, OR

EVENT REGION California, Nevada, Oregon, and Washington

PARTICIPANT LIST Katharine Thomas, MD | Cannon Milani, MD | Jason Suh, MD

CASE SUMMARY

A 67-year-old man was referred from a dermatologist. He was referred initially to the dermatologist by his primary care physician for progressive, persistent cutaneous nodules that the patient first noticed 3 weeks prior. The patient had fatigue and 5-kg weight loss over 3 months and a medical history of sinusitis but no major comorbidities. Physical examination was notable for multiple purpuric nodules (measuring up to 5 cm on arms, legs, and torso). No palpable adenopathy or hepatosplenomegaly was observed. His ECOG performance status was 1.

Laboratory results:

• White blood cell count: 14.1 × 10³/μL
• Hemoglobin: 8.9 g/dL
• Platelets: 54 × 10³/μL
• Differential revealed 12% blasts, 32% neutrophils, 16% monocytes, and 40% lymphocytes.

On a peripheral blood smear, there were blastic cells with large and round or slightly irregular nuclei; blast cytoplasm stained grayish-blue without granules or Auer rods. A bone marrow biopsy result showed 40% blasts by morphology and 80% cellular marrow with interstitial infiltrate. Immunohistochemistry result of neoplastic cells showed positive CD123, CD4, CD56, and TCL1. Flow cytometry result showed negative CD4, CD56, CD123, CD34, and T- and B-cell lineage-specific markers. The patient had 46,XY cytogenetics. A lumbar puncture did not indicate central nervous system involvement. The patient was ultimately diagnosed with blastic plasmacytoid dendritic cell neoplasm (BPDCN) based on clinical and histopathological findings.

DISCUSSION QUESTIONS

• If a patient presented to you with severe skin manifestations, how would you approach diagnostic workup?
• What possible hematologic malignancies come to mind?

THOMAS: Another [disease besides BPDCN] that comes to mind would be Sweet syndrome.

LACHOWIEZ: I agree. I was looking through the differential, and I was a bit surprised that neutrophilic dermatoses weren’t on it. We see a lot of Sweet syndrome with hematologic malignancies, so that should be on there. Anything else come to mind?

MILANI: I thought of angiosarcoma. I have a couple of cases in terms of scalp-riddled angiosarcoma. I treat a lot of sarcoma here in Los Angeles, California, at Kaiser Permanente.… This was a great case presentation for me because I was not thinking about this entity prior to today’s talk. It’s reassuring to know there are other potential areas of involvement.

LACHOWIEZ: That’s wonderful to hear. Angiosarcoma can have cutaneous findings, [as] you mentioned. Kaposi sarcoma [can have cutaneous findings] in some of our patients with HIV or AIDS as well, in particular if they’re not on HAART [highly active antiretroviral therapy]. Acute myeloid leukemia [AML] with cutaneous involvement or extramedullary disease could [also present as severe skin manifestation].

For the basic evaluation and workup of BPDCN, as with every other cancer that we treat, history, physical, and basic metabolics are important. What is unique to this disease is the skin analysis, so expert consultation with dermatology is recommended.¹ Skin biopsy is not one of the 100% necessary criteria, but you’d be hard pressed to find any oncologist who would not [perform biopsy on a large, visible] lesion, and it can be particularly helpful.

CASE UPDATE

• The patient received tagraxofusp (Elzonris) at 12 μg/kg per package label for frontline therapy.
• He achieved complete response (CR) after 1 cycle of therapy.

DISCUSSION QUESTION

• What are your impressions of the data from the phase 1/2 study (NCT02113982) of tagraxofusp for BPDCN?

SUH: The overall response and CR rate are very high.² Most of the antibody treatment is not this effective, even though it does not last long. You can use [tagraxofusp] as induction for the transition to allogeneic transplantation, so this is a good treatment option.

LACHOWIEZ: In general, that’s a fair statement, and I would agree if the goal is to get these patients into first CR. In first CR, I would advocate for an allogeneic transplant if the patient is fit enough to receive it. You are right: The remission duration can be fleeting. Based on the long-term results of the tagraxofusp study, it can last for a while, but unfortunately, most of these patients are going to [experience] relapse.

I worry about the capillary leak syndrome. We’ve been fortunate we haven’t had any severe cases of it, but does the adverse event profile of this medication turn anyone off to it? My impression is that I worry about it, but I also realize this is a horrible disease that we have few treatment options for, and with informed consent, I think everyone understands what treatment entails.

SUH: We can deal with it. If the [capillary leak] syndrome is significant, we’ll end up putting the patient in the hospital to give albumin and do conservative management, as you said. Otherwise, the prognosis is horrible, so we don’t have any other options. I think it’s much easier than intensive chemotherapy [such as] hyper-CVAD [cyclophosphamide, vincristine, doxorubicin hydrochloride (Adriamycin), and dexamethasone] or conventional 7 + 3 chemotherapy. They would be in the hospital for almost a month. Compared with that induction, this is much easier.

LACHOWIEZ: I think that’s reasonable, and I would agree with that.

CASE UPDATE

• The patient continued tagraxofusp with maintenance of CR for 12 months.
• ECOG performance status: 1
• His family inquired about additional therapeutic optionsfor maintaining long-term remission.

DISCUSSION QUESTION

• What are your thoughts on stem cell transplant (SCT) bridging therapy when considering treatment with tagraxofusp for your patients with BPDCN?

LACHOWIEZ: Patients who achieved a composite CR and then went on to SCT…had a median overall survival [OS] of 38.4 months [range, 3.4-58.1], with a 24-month OS [rate] of 66%.2 These are great numbers. There were 72% of patients who appeared to be responding well to the regimen [who] had a remission for longer than 12 months post SCT. These data would suggest that we should advocate for patients who attain a remission, if they’re fit enough for it, to proceed to SCT. Four of the 18 patients [who did not receive SCT] experienced this prolonged duration of response greater than 6 months. Two of these 4 had very long responses—27 and 52 months, respectively. That’s wonderful, but that’s the minority and a bit of an exception to the rule.

The main thing is every institution is slightly different. I’m a leukemia [physician], so I don’t do transplants. At our institution, I work very closely with a group of transplanters who can have this discussion with the patient and explain to them what an allogeneic SCT entails. We work in close coordination with them. At other centers, [sometimes oncologists] are both the primary treating physician as well as the transplant physician. Some of you may be well equipped to have this conversation. But having these patients cared for at a large tertiary care center, if possible, where we can consolidate their care under 1 roof and have these complex discussions, is a good idea.

There are not a lot of data in BPDCN with allogeneic SCT, but the data that we have out of The University of Texas MD Anderson Cancer Center [in Houston] look promising for these patients. The median is approximately 20 months for progression-free survival [PFS] and pushes median OS out to approximately 30 months.³ But when we look at the subset of patients who attained a true CR following tagraxofusp therapy, we see the PFS and OS curves look great for these patients. We just have to be cautious here. There are only 10 patients in these studies, and that speaks to the rarity of the disease. But it at least gives us some data to show that patients can have good outcomes when they’re bridged to transplant with tagraxofusp.

SUH: I presume that these patients got tagraxofusp before the transplantation but not after, right?

LACHOWIEZ: That’s a good question. I do not believe there was any tagraxofusp maintenance, [but I am not sure].

SUH: That’s a very tempting concept, because [with] allogeneic SCT, at least 30% to 40% of the patients are having a relapse. These are antibody treatments, so by giving some more treatment after transplantation, they might do better.

LACHOWIEZ: It’s a wonderful concept. Some of our post-transplant maintenance studies for AML have not panned out the way we would have expected them to, but I still think there’s room for posttransplant maintenance. It depends on the patient population and the disease. I don’t know in this patient population whether they received tagraxofusp post transplantation. That’s a good question.

CASE UPDATE

• After consultation with transplant team, the patient declined allogeneic hematopoietic cell transplant.
• Twenty-two months after starting tagraxofusp, relapse was documented with recurrence of skin lesions and evolving pancytopenia.
• ECOG performance status: 1

LACHOWIEZ: There’s no standard [treatment for patients with BPDCN], so clinical trials are preferred.¹ Tagraxofusp, if it wasn’t used, can be used in this setting. Chemotherapy and AML, acute lymphoblastic leukemia, and lymphoma-directed regimens are appropriate in this setting. Venetoclax [Venclexta]-based therapy is in the National Comprehensive Cancer Network guidelines in the relapsed setting. It’s not yet in the frontline setting. All patients should still be evaluated for central nervous system disease, and if they are fit enough for transplant and declined it for whatever reason in first CR, transplant should be reconsidered in the salvage setting.

DISCUSSION QUESTIONS

• What does BPDCN relapse/disease progression look like?
• What are some treatment options for patients who experience progression on tagraxofusp?

LACHOWIEZ: Probably the main treatment paradigm that we’re using in the few patients we’ve treated at Oregon Health & Science University in Portland is tagraxofusp in the frontline setting. Because of the sensitivity of BPDCN to BCL2 antagonists, such as venetoclax, [we use] a combination of azacitidine/venetoclax or decitabine/venetoclax. Intensive chemotherapy does have a lot of toxicity, and this is an older patient population. Typically, BPDCN can be very symptomatic and [affect] performance status to a degree as well as have organ involvement that can objectively make the receipt of intensive chemotherapy harder. For that reason, I favor tagraxofusp followed by a lower-intensity venetoclax-based regimen and then transplant if possible.

There are ongoing clinical trials in this disease space. Despite it being a rare disease, there are newer anti-CD123–directed therapies.⁴ There’s a CD123 chimeric antigen receptor that’s in clinical trials currently. XmAb 14045 is a bispecific they’re looking at in BPDCN; it’s more of an umbrella trial of any patient with a CD123-positive myeloid malignancy. If you encounter these patients and they’re not responding or they [experienced relapse] following standard-of-care therapies, I would highly advise everyone to look for a trial and get on ClinicalTrials.gov and see what’s out there.

_REFERENCES

_{1. NCCN. Clinical Practice Guidelines in Oncology. Acute myeloid leukemia, version 6.2023. Accessed February 6, 2024. http://tinyurl.com/yusas35n}

_{2. Pemmaraju N, Sweet KL, Stein AS, et al. Long-term benefits of tagraxofusp for patients with blastic plasmacytoid dendritic cell neoplasm. J Clin Oncol. 2022;40(26):3032- 3036. doi:10.1200/JCO.22.00034}

_{3. Bashir Q, Milton DR, Popat UR, et al. Allogeneic hematopoietic cell transplantation for patients with blastic plasmacytoid dendritic cell neoplasm (BPDCN). Bone Marrow Transplant. 2022;57(1):51-56. doi:10.1038/s41409-021-01478-5}

_{4. Pemmaraju N, Kantarjian H. Blastic plasmacytoid dendritic cell neoplasm: emerging developments and special considerations for 2023. Clin Adv Hematol Oncol. 2023;21(5):257-264.}